Bipolar disorder is a severe mental disorder with limited pharmacological treatment because the pathophysiology of this severe mental illness is poorly understood. No definitive mechanism of action of available mood stabilizers has been identified, which limits the development of new mood stabilizing agents. Extensive studies in vitro and in cultured cells have shown that lithium and valproate modulate glycogen synthase kinase-3beta (GSK3beta), a unique protein kinase that is under inhibitory control by several signaling systems. Although GSK3beta is a prime candidate therapeutic target of mood stabilizers, there is limited evidence of in vivo regulation of GSK3beta by mood stabilizers, and its relevance to the therapeutic effects of mood stabilizers in bipolar disorder remains to be established. The objective of this project is to identify the in vivo regulatory effects of the available mood stabilizers on GSK3beta and the associated signaling systems, specifically the upstream PI3K/Akt signaling pathway and the downstream target transcription factor CREB. The central hypothesis for the proposed research is that GSK3beta is a central component of the mechanisms of action of lithium and other mood stabilizers in vivo. The Specific Aim of this two-year project is to test the hypothesis that lithium and other anticonvulsant mood stabilizers modulate GSK3beta in the brain and in peripheral lymphocytes of mice. The working hypotheses include that chronic treatments with therapeutically relevant doses of lithium, valproate, and lamotrigine inhibit GSK3beta in mouse brain, the mechanisms of action of the mood stabilizers may involve regulating GSK3beta or the PI3K/Akt signaling pathway, with a common consequence of regulating the transcription factor CREB, and the effect of lamotrigine on GSK3beta may be related to its blocking effects on glutamate release. If GSK3beta represents an important therapeutic target of mood stabilizers, it is important to test if changes occurring in mouse brain are also detectable in mouse lymphocytes, since this will be a basis for future testing of similar changes in humans. This study will apply knowledge obtained from in vitro studies of GSK3beta to in vivo studies of mouse brain, and for the first time proposes to identify the in vivo actions of mood stabilizers on GSK3beta and the associated PI3K/Akt signaling pathway as potential therapeutic targets of mood stabilizers. The proposed research is expected to provide significant new insight into the pathophysiology and treatment of bipolar disorder. The data obtained from this proposal will be used to support a future R01 grant application to achieve our long-term goal of understanding the pathophysiology and improving the treatment of bipolar disorder.